Multiple sclerosis (MS) is an inflammatory disease of the central nervous system affecting 0.1% of the population, and is associated in northern European caucasoid MS patients with the HLA-DR-2 (DRB1*1501) haplotype (Olerup, O. et al. 1991. Tissue Antigens 38:1-15). An animal model of MS, experimental autoimmune encephalomyelitis (EAE), is a T cell-mediated autoimmune disease. EAE can be induced by subcutaneous injection of peptides derived from myelin components such as myelin basic protein (MBP; Madsen, L. S. et al. 1999. Nat. Genet. 23:343-347), proteolipid protein (PLP; Greer, J. M. et al. 1992. J. Immunol. 149:783-788) or myelin oligodendrocyte glycoprotein (MOG; Mendel, I. et al. 1995. Eur. J. Immunol. 25:1951-1959).
In the course of EAE, autoreactive CD4+ T cells recognize self-antigens presented by murine class II MHC molecules (e.g. H-2As), ultimately leading to pathological changes that can be monitored as clinical signs of disease. EAE provides a well studied system for testing the efficacy of potential therapeutic compounds to suppress the disease. These compounds have included cytokines (Leonard, J. P. et al. 1996. Ann. N.Y. Acad. Sci. 795:216-226), peptide antigens that induce anergy (Gaur, A. et al. 1992. Science 258:1491-1494) or that induce oral tolerance (Kennedy, K. J. et al. 1997. J. Immunol. 159:1036-1044; Weiner, H. L. Exp. Med. 181:1569-1574; Nicholson, L. B. et al. 1997. Proc. Natl. Acad. Sci. USA 94:9279-9284).
Copolymer 1 (Cop1; Copaxone®; YEAK) is a random amino acid copolymer of alanine (A), lysine (K), glutamic acid (E) and tyrosine (Y) in a molar ratio of approximately 5:3:1.5:1. Cop1 is synthesized in solution using N-carboxyamino acid anhydrides (Teitelbaum D. et al. 1971. Eur. J. Immunol. 1:242-248). Initially, this and other related copolymers were used to define the genetic basis of immune responsiveness, now known as class II MHC genes (McDevitt, H. O., and M. Sela. 1965. J. Exp. Med. 122:517-532; McDevitt, H. O., and M. Sela. 1967. J. Exp. Med. 126:969-978). Cop1, also known as poly (Y,E,A,K) or YEAK was found to be effective both in suppression of experimental allergic encephalomyelitis (Teitelbaum D. et al. 1971. Eur. J. Immunol. 1:242-248; Teitelbaum D. et al. 1973. Eur. J. Immunol. 3:273-279; Teitelbaum D, et al. 1974; Clin. Immunol. Immunopathol. 3:256-262; Aharoni R. et al. 1993. Eur. J. Immunol. 23:17-25) and in the treatment of relapsing forms of multiple sclerosis (MS; Bornstein, M. B. et al. 1987. N. Engl. J. Med. 317:408-414; Johnson, K. P. et al. 1995. Neurology 45:1268-1276; Johnson, K. P. et al. 1998. Neurology 50:701-708).
Cop1 has been approved as a therapy for MS and currently is in wide use. However, while Cop1 reduces the MS relapse rate, it does not eliminate relapse, and is not curative for the disease. It is important to develop improved compositions and methods of use for treatment of MS, and for other autoimmune diseases.